Project Abstract/Summary To date, there is no effective treatment for eradicating high risk human papilloma virus (HR-HPV) systemic infections. Current treatment modalities are directed at alleviating local symptoms and removing symptomatic lesions or dysplasia. Often, treatment is delayed until the HPV lesions enlarge and the patient becomes symptomatic. In many cases, patients are treated by the physician employing cryotherapy, surgical excision, or electrosurgery. This local treatment removes the lesion but does not clear the systemic infection thus patients will frequently have recurrent lesions. Persistent HR-HPV infections occur in approximately 10% of population, and these are the patients that have an increased risk for developing cancer. In recent years, cancer research has focused on the significance of persistent HR-HPV infections with in the pathogenesis of multiple cancer as well as impact on response to treatment and prognosis. The long?range goal of this research is to develop effective treatment regimen to eradicate HPV and prevent development of HPV-related cancers. The objective of this application is to determine the feasibility of using a safe, readily available nutritional supplement for the eradication of HR-HPV infections; specifically confirming efficacy and durability of response of the regimen of AHCC (active hexose correlated compound) 3 g r a m s o n c e d a i l y supplementation for six months that was determined from a dose-finding pilot study to eradicate HR-HPV infection. This will be achieved with a randomized, double-blinded, placebo controlled phase II study in women over the age of 30 years with confirmed persistent high-risk HPV infections. The central hypothesis of this proposal is that modulation of host immune response leads to facilitating clearance of persistent HPV infections. The rationale for the proposed research is that emerging preclinical data has demonstrated in our pilot study as well as other knock-out animal models, that the suppression of interferon beta (IFN-? ) in presence of chronic infection associated rebound upregulation of IFN-gamma (IFN-?) enabling host immunity to clear the viral infection. The proposed work is innovative because our pilot study is the first human data to demonstrate that the unique suppression of IFN-? was associated rebound upregulation of IFN-gamma and ultimate clearance of persistent HPV infections. Currently only local treatments are readily available for treatment of complications from HPV infections. Use of a safe, readily available nutritional supplement that modulates host immunity to enable natural clearance of persistent HR-HPV infections would significantly impact patient outcomes for both men and women. The results of this study will be significant in reducing the development of short-term dysplasia and ultimately the long-term risk of developing cancer.